Enzyme Replacement Therapy

The mucopolysaccharidoses (MPS) are a heterogeneous group of in-born metabolic conditions caused by genetic defects that result in the absence or severe deficiency of one of the lysosomal hydrolases responsible for the degradation of glycosaminoglycans (GAGs). Such enzyme deficiency causes accumulation of GAGs that begins in infancy and progressively worsens, often affecting several organs including the central nervous system (CNS) inducing mental retardation, progressive neurodegeneration, and premature death. Over the last years, enormous progress has been made in the treatment of many MPS types, and available treatments are efficacious for many of them. Nevertheless, treatment of MPS with CNS involvement is limited mostly because of delivery impediments related to the presence of the blood-brain barrier (BBB). This chapter presents an overview of the BBB and of the different strategies that have been developed to overcome the problem of drug transport at the BBB, assuring efficient delivery of therapeutic agents to the brain.

Enzyme replacement therapy (ERT) is available for mucopolysaccharidosis (MPS) I, MPS II, MPS VI, and MPS IVA. The efficacy of ERT has been evaluated in clinical trials and in many post-marketing studies with a long-term follow-up for MPS I, MPS II, and MPS VI. While ERT is effective in reducing urinary glycosaminoglycans (GAGs) and liver and spleen volume, cartilaginous organs such as the trachea and bronchi, bones and eyes are poorly impacted by ERT probably due to limited penetration in the specific tissue. ERT in the present formulations also does not cross the blood-brain barrier, with the consequence that the central nervous system is not cured by ERT. This is particularly important for severe forms of MPS I and MPS II characterized by cognitive decline. For severe MPS I patients (Hurler), early haematopoietic stem cell transplantation is the gold standard, while still controversial is the role of stem cell transplantation in MPS II. The use of ERT in patients with severe cognitive decline is the subject of debate; the current position of the scientific community is that ERT must be started in all patients who do not have a more effective treatment. Neonatal screening is widely suggested for treatable MPS, and many pilot studies are ongoing. The rationale is that early, possibly pre-symptomatic treatment can improve prognosis. All patients develop anti-ERT antibodies but only a few have drug-related adverse reactions. It has not yet been definitely clarified if high-titre antibodies may, at least in some cases, reduce the efficacy of ERT.

The aim of this review is to summarize the evidence on efficacy, effectiveness and safety of intravenous enzyme replacement therapy (ERT) available for mucopolysaccharidoses (MPSs) I, II, IVA, VI and VII, gained in phase III clinical trials and in observational post-approval studies. Post-marketing data are sometimes conflicting or controversial, possibly depending on disease severity, differently involved organs, age at starting treatment, and development of anti-drug antibodies (ADAs). There is general agreement that ERT is effective in reducing urinary glycosaminoglycans and liver and spleen volume, while heart and joints outcomes are variable in different studies. Effectiveness on cardiac valves, trachea and bronchi, hearing and eyes is definitely poor, probably due to limited penetration in the specific tissues. ERT does not cross the blood-brain barrier, with the consequence that the central nervous system is not cured by intravenously injected ERT. All patients develop ADAs but their role in ERT tolerance and effectiveness has not been well defined yet. Lack of reliable biomarkers contributes to the uncertainties about effectiveness. The data obtained from affected siblings strongly indicates the need of neonatal screening for treatable MPSs. Currently, other treatments are under evaluation and will surely help improve the prognosis of MPS patients.

IntroductionPompe disease, a rare autosomal recessive lysosomal storage disorder, results from mutations in the GAA gene that lead to deficient acid alpha-glucosidase activity and glycogen accumulation in various tissues.MethodsThis review employs the diagnostic approach to the disease, encompassing enzymatic assays and molecular genetics, with a focus on genotype-phenotype correlations and regionspecific mutations.ResultsOver 500 mutations in the GAA gene, including missense, nonsense, insertions, deletions, and splicing defects, contribute to varying levels of enzyme deficiency, accounting for the diverse clinical manifestations of Pompe disease.DiscussionCurrent therapies, including Enzyme replacement therapy (ERT), are the cornerstone treatments for Pompe disease, utilizing recombinant human alpha-glucosidase to restore enzyme activity and reduce glycogen accumulation in lysosomes. While ERT significantly improves survival, cardiomyopathy, and respiratory function, its limited uptake in skeletal muscle and immunogenicity pose challenges. Innovations include immune tolerance protocols and nextgeneration enzymes to enhance skeletal muscle delivery. Gene therapy emerges as a promising alternative, leveraging viral vectors to deliver functional GAA genes, thereby enabling sustained endogenous enzyme production and addressing limitations of ERT. Preclinical and early-phase trials demonstrate efficacy, reduced immunogenicity, and enhanced skeletal muscle uptake; however, challenges, such as vector immunogenicity and cost, remain. Thus, genetic counseling is essential for family planning and managing emotional and psychosocial challenges related to this disease.ConclusionThis article highlights advances and challenges in the diagnosis, management, and treatment of Pompe disease, providing a comprehensive resource for clinicians and researchers.